This application describes a method of topically treating skin with iodine to kill pathogens in and on the epidermal surface of the skin without irritating the skin and without leaving a visable skin discoloration and to non-staining topical iodine compositions that provide antimicrobial persistence for the disinfection of topical pathogens and for treatment and/or prevention of skin infections and diseases.
Tincture of iodine was first used as a topical disinfectant in 1839. Tincture of iodine and subsequent iodine compositions, like Lugol""s solution, are topical irritants that stain human skin. The invention of povidone iodine in 1956 (U.S. Pat. No. 2,739,922), commonly referred to as xe2x80x9ctamedxe2x80x9d iodine, eliminated the topical irritancy associated with iodine but not the staining.
Povidone iodine contains very low (1-10 ppm) concentrations of molecular iodine (I2) and high concentrations of triiodide (I3xe2x88x92≈10,000 ppm) and iodide (Ixe2x88x92≈5,000 ppm). Such compositions are referred to as xe2x80x9ccomplexedxe2x80x9d iodine. Complexed iodine generically refers to compositions wherein molecular iodine is complexed with organic molecules and/or iodide. Molecular iodine is complexed in order to increase shelf-life and reduce irritation. It is currently described in the literature and believed by those skilled in the art that molecular iodine is the iodine species responsible for epidermal irritancy and staining. By lowering the concentration of molecular iodine it is believed that the irritancy and staining of iodine is minimized.
Many inventions that rely upon complexed iodine have been made in the field of topical iodine compositions. Iodine is complexed by contacting a source of diatomic iodine (I2) with a polymeric material having large segments of polymeric residues derived from ethylene oxide, propylene oxide or other alkylene oxides in the form of block polymer chains. Examples include ethoxylated surfactants, cellulose, cellulose derivatives and polyvinyl pyrrolidone components. The alkoxylated (usually ethoxylated) surfactants include, but are not limited to, the group consisting of alkylphenol ethoxylates, ethoxylated fatty acids, alcohol ethoxylates, alcohol alkoxylates, polysorbates (ethoxylated sorbitol) and ethylene oxide-propylene oxide copolymers (commonly called Poloxamers as described in U.S. Pat. No. 5,368,868). A preferred source of iodine for reaction with nonionic materials to form iodine complexes is a composition comprising iodine in association with an inorganic iodide which provides a source of xe2x80x9cactivexe2x80x9d iodine. Such a source is described in Winicov, U.S. Pat. No. 3,028,299, Cantor et. al. U.S. Pat. No. 3,728,449, Schmidt W. et. al. U.S. Pat. No. 5,503,838, Brink et al. U.S. Pat. No. 5,173,291, and McKinzie M. et al., U.S. Pat. No. 5,529,770. Commonly, at least 0.35 parts of iodide (Ixe2x88x92) are present per part of diatomic iodine.
Topical application of biocidal agents has been accomplished using solutions, ointments and physical appliances. To provide prolonged antisepsis, it is usually necessary to repeatedly apply an iodine topical agent since microorganisms may survive the initial application. Topical iodine biocides are usually water soluble which leads to their removal from the epidermis by contact with water or bodily fluids. Increasing the water and bodily fluid resistance of topically applied iodine agents and thereby increasing the substantivity and length of bactericidal activity has been a long-standing goal in the art. This invention teaches against compositions that impart a highly visible iodine coloration to the epidermis such as that derived from complexed iodine and further discloses formulation constraints to provide a persistent non-irritating topical iodine disinfectant that does not stain. Such compositions have several commercially useful properties. The iodine compositions of this invention are not materially affected by water and body fluids and provide long lasting efficacy. Also, the compositions of this application provide iodine in a form that is capable of penetrating the skin and inactivating pathogens that reside within and on the skin.
The term xe2x80x9cmolecular iodinexe2x80x9d as used herein refers to diatomic iodine, which is represented by the chemical symbol I2, which is not complexed with other molecules so that it is free to diffuse into epidermal tissue.
The term xe2x80x9ccomplexed iodinexe2x80x9d as used herein, refers to free molecular iodine that is combined with an organic carrier or with iodide anions to form triiodide such that the chemical activity of free molecular iodine is reduced. The complexed iodine is preferably prepared by combining diatomic iodine and a complexing agent.
The term xe2x80x9ciodide anionxe2x80x9d as used herein, refers to the species that is represented by the chemical symbol Ixe2x88x92. Suitable counter-ions for the iodide anion include sodium potassium and the like.
The term xe2x80x9ctriiodidexe2x80x9d as used herein, refers to the species which is represented by the chemical symbol I3xe2x88x92. It is recognized by one skilled in the art that triiodide can dissociate into one iodide anion and one molecule of free molecular iodine.
The term xe2x80x9ctotal iodinexe2x80x9d as used herein, refers to the following iodine species: free molecular iodine, iodide, organically complexed forms of iodine and triiodide.
The term xe2x80x9crate of iodine generationxe2x80x9d as used herein, refers to the rate at which molecular iodine is formed.
The term xe2x80x9cratio of molecular iodinexe2x80x9d as used herein, refers to the ratio of molecular iodine (I2) to other iodine species such as iodide and triiodide.
It has been believed that molecular iodine is an irritant and responsible for the staining of skin associated with the use of topical iodine compositions. We have observed that complexed iodine, not molecular iodine, is the species of iodine that is primarily responsible for skin staining in commercially available iodine compositions. We have further observed that it is possible to formulate compositions that will deliver molecular iodine into the epidermis and not stain or irritate skin. Once molecular iodine penetrates into the skin, it maintains its biocidal activity while in the skin and can diffuse back out of the skin (W. Gottardi, Journal of Hospital Infection, Vol. 29, page 9, 1995). Such back-diffusion provides a long-lived chemical barrier that is resistant to water and body fluids.
This application describes the formulation constraints necessary to provide a topical iodine disinfectant that will not irritate or stain epidermal tissue but will otherwise kill pathogens on the epidermis; these formulation constraints apply to the following forms of iodine: molecular iodine, iodide, triiodide and complexed iodine. The teachings and examples in this application do not make any attempt to specifically enumerate all of the prior art in the area of topical iodine preparations. Excipients that are known to be compatible with complexed iodine may also be of use with compositions and conditions described in this application. Such excipients include surfactants, thickeners, film forming agents, penetrants, humectants, emollients, dyes, skin conditioning agents, stabilizing agents, opacifiers, wetting agents, chelating agents, buffers, organic acids and fragrances.
Topical disinfectants are used to inactivate pathogenic organisms that are present on the epidermis and to prevent pathogenic organisms from populating the epidermis. A preferred topical disinfectant will (a) not irritate or stain the epidermis, (b) have a broad spectrum of activity, (c) rapidly inactivate pathogens, (d) provide residual activity for 2 to 8 hours, (e) resist water and bodily fluids, and (f) prevent pathogenic organisms from repopulating the epidermis. To date there are no perfect topical antimicrobial compositions in commerce. The compositions described in this application are based on defined ratios of free molecular iodine to total iodine and provide, in combination with other excipients, the basis for preferred topical disinfectants.
Iodine compositions, as compared to topical compositions based on other active agents, have a material disadvantage in that they stain skin. Typical iodine stains are reddish brown or yellowish in color and these stains do not readily dissipate from the epidermis. It has long been assumed that the form of iodine that stains the skin is molecular iodine. We have observed that this is not true and that most of the staining from iodine compositions is due to triiodide as demonstrated in the Examples of this application.
For purposes of this application, a stain is a yellowish-brown coloration of the skin that does not completely dissipate after a defined time period. The relevant time period for dissipation of a stain will vary with the intended application. For instance, if a topical disinfectant is applied to the faces of adolescent girls several times a day, then any coloration that may be present should dissipate within 1 minute. If a topical antifungal composition is formulated for use on toes and applied prior to sleeping then any coloration should dissipate within 6 hours. If a topical iodine composition is formulated for use on cow teats to prevent mastitis and applied after milking then coloration can remain for at least 30 minutes post application.
It is obvious to one skilled in the art that there is a wide variation between people with respect to the degree of staining their skin will experience from iodine-based topicals. We have also observed that the degree of staining is a function of the carrier that contains the iodine. For instance, isopropyl myristate, which facilitates the penetration of agents into the epidermis, reduces the degree of coloration from free molecular iodine. Also, the degree of staining from topical iodine compositions that are liquids is a function of the application time. The longer a liquid is in contact with the epidermis, the more pronounced the staining.
The most preferred compositions anticipated by this application will not produce any coloration of the epidermis. The preferred compositions of this application will produce a mild iodine coloration that is dissipated within 10 minutes. The range of compositions anticipated by this application will produce an iodine-mediated coloration that is dissipated within 3 hours. It is recognized by one skilled in the art that it may be useful for the compositions contemplated in this application to temporarily impart a color. For instance, it may be of use to a surgeon to view a color on skin prior to opening an incision. Such a coloration provides evidence that the site is disinfected.
The concentration of molecular iodine contemplated in this application ranges from 15 ppm up to 330 ppm within a pH range of 3.0 to 7.5. The preferred concentration of molecular iodine is from 25 ppm to 175 ppm. The most preferred concentration of molecular iodine is from 25 to 100 ppm.
Numerous methods known in the art can be utilized to form molecular iodine. For in situ generation of iodine from iodide the most common oxidants are active chlorine compounds and hydrogen peroxide. However, in the latter case a catalyst is necessary to speed up the formation of iodine. Other iodine generating compounds have been used including iodine pentoxide and tetraglycine hydroperiodide. Molecular iodine can also be generated by dilution of formulations that contain complexed iodine or by dissolution of elemental iodine as is done in several devices utilized for water disinfection.
Molecular iodine can be generated in situ in an aqueous medium by combining a source of peroxidase, a source of hydrogen peroxide and an iodide. This combination is known to be bactericidal. This bactericidal activity results from the enzymatic reaction that occurs when peroxidase, hydrogen peroxide and iodide react in solution at a controlled pH between pH 3.0 and 7.5. Peroxidase is known to effect the transfer of electrons from iodide to hydrogen peroxide. Hydrogen peroxide is converted into water by this reaction. The preferred oxidant of this invention is hydrogen peroxide. Any material that acts as a source of hydrogen peroxide when admixed in an aqueous environment is suitable for this application. The term xe2x80x9csource of peroxidexe2x80x9d for purposes of the present invention and as used herein shall mean any material alone or in combination which can serve as precursors for hydrogen peroxide including metal peroxides, percarbonates, persulphates, perphosphates, peroxyesters, urea peroxide, peroxyacids, alkylperoxides, acylperoxides and perborates. Alternately methyl, ethyl and other higher molecular weight peroxides can be used as a source of hydrogen peroxide but these are not preferred. Mixtures of two or more of these substances can also be used. The preferred concentration for hydrogen peroxide is between 0.001 and 0.1% in the final composition prior to initiation of the oxidation of iodide.
Suitable dry sources of iodide anion include sodium iodide and potassium iodide as well as other salts of iodide. Any compound that yields iodide anion upon dissolution in an aqueous environment is suitable for this application. The simple salts of iodide are preferred and have the advantage of being less costly. Additionally, they have a long shelf life in solid and liquid form.
The enzyme peroxidase is identified by the International Union of Biochemistry and the International Union of Pure and Applied Chemistry by the Enzyme Commission identification No. E.C. 1.11.1.7 although certain members of E.C. 1.11.1.8 can also be used. These classes of peroxidase can be obtained from a wide variety of sources including milk (lactoperoxidase), soy bean, and human leukocytes (myerloperoxidase). Within these two E.C. classes the further requirement for a suitable peroxidase as defined in this application is that it is capable of oxidizing iodide to iodine within the pH range of 3 to 7.5. The least expensive peroxidases suitable for this application is horseradish peroxidase and soybean peroxidase. It is anticipated that peroxidase that has been cloned from either horseradish, milk or human leukocytes or other sources will be suitable as a source of peroxidase for this application. Additionally, it has been observed that chemically modified peroxidase is suitable for use in this application. Modifications to the amino, carboxyl or carbohydrate moieties yield a suitable catalytic agent for inclusion in this application. The chemical modifications to peroxidase include cross-linking of enzyme molecules to each other, to solid surfaces or to other proteins. The chemical agents used for crosslinking include glutaraldehyde, maleimides, succinimides, carbodiimides, dicarboxylates, activated glycols, imidoesters, photoreactive azides and other agents known to one skilled in the art.
This application teaches that the concentration of triiodide should be minimized in order to minimize staining as demonstrated in the Examples of this disclosure. It may be necessary to formulate a composition at a particular pH and to incorporate certain additives that necessitate the incorporation of triiodide or promote the formation of triiodide. In other words, it is not always possible to eliminate triiodide from compositions of matter that contain substantial concentrations of molecular iodine. However, in accordance with the present invention it is necessary to carefully maintain the concentration of triiodide at below a preferred maximum level in order to minimize staining.
The complexing of molecular iodine by iodide ion has long been of major interest, and studies of this subject have used solubility, distribution and potentiometric, conductimetric, and spectrophotometric techniques. As a result, the factors that govern the formation of triiodide are well known in the art. In 1965, Ramette and Sandford (Journal of the American Chemical Society, Vol. 87(22), pages 5001-5) published a study, herein incorporated by reference, that provides an analysis of the factors that govern the formation of triiodide in addition to an empirical algorithm that accurately predicts the concentration of triiodide under a variety of conditions. As a practical matter, it is very useful to measure the concentration of molecular iodine as well as the concentration of triiodide and to correlate these measurements with the total mass of iodine known to be present in a composition.
The concentration of triiodide contemplated in this application ranges from 0 ppm up to a maximum of 700 ppm. The preferred concentration of triiodide should range from 0 ppm to 100 ppm. The most preferred concentration of triiodide should range from 0 to 50 ppm.
Complexed forms of iodine (e.g., polyvinylpyrrolidone iodine) other than triiodide can also stain skin. It is well known that 10% polyvinylpyrrolidone iodine forms a film on skin when it dries and that this film is highly colored. When the compositions of this invention also contain a complexed form of iodine, the sum of the concentrations of iodine complexed with organic compounds and triiodide should be limited to a maximum not to exceed 700 ppm under any circumstances. Iodide does not cause staining of skin. The concentration of iodide is not a critical aspect of staining but it will effect the concentration of molecular iodine and triiodide.
The types of compositions contemplated under this application include liquids, gels, creams, ointments and emulsions. The type of composition is not a determinative aspect of this application rather the absolute and relative concentration of molecular iodine and complexed iodine are the two most critical aspects of this invention. Examples of the different types of compositions are provided, by way of example, in the Examples section of this application. It is clear from these experiments that many different types of compositions are compatible with the teachings of this application.
Dermatological compositions frequently form a film over the epidermis. Such a film can provide added physical protection and serve to increase the emolliency of the topical composition. A good film-forming composition should be dermatologically acceptable and capable of application conveniently in a water based mixture which dries quickly on skin. The film should be water and body fluid resistant and permit facile transmission of water vapor. The film should adhere suitably to epidermis and be capable of facile removal from said epidermis. The film should be soluble in a dermatologically acceptable solvent such as water or a lower alkyl alcohol which may be used as or in a remover solution which could be employed to remove the film when desired. The film contemplated in this application is, when dry, about 0.002 mm to 0.05 mm thick.
The surfactants useful in the context of this application include anionic surfactants such as carboxylate, sulfonate, and sulfate materials including carboxylate surfactants such as potassium alkyloxycarboxylates, an alkyl sarcosinates, alkyl benzene sulfonates, alpha olefin sulfonates, and sulfonates with an ester amide or ether linkage. Additionally useful surfactant agents include sulfated alcohol, sulfated alcohol ethoxylates, sulfated alkyl phenols, sulfated carboxylic acid amides and esters, sulfated natural oils and fats as well as agents such as dioctyl ester sodium sulfosuccinic acid.
The thickeners useful in the context of the invention are preferably taken from the group consisting of alkyl celluloses, the alkoxy celluloses, xanthan gum, guar gum, polyorgano sulfonic acid and mixtures thereof. The thickeners are chosen based on compatibility with the other formulation ingredients and desired viscosity. Generally speaking the thickener should be present at a level of from about 0.01-10% by weight, and more preferable from about 0.1-1% by weight.
The penetrants useful in the context of the invention include isopropyl myristate, polyethylene glycol, and propylene glycol. Generally speaking the penetrant should be present at a level of from about 0.1 to 4% by weight.
Generally, any dispersible skin conditioning agent, humectants and emollients, known to those of skilled in this art may be used in the present invention. Preferred emollients to be used in the invention are taken from the group consisting of glycerin, propylene glycol, sorbitol, lanolin, lanolin derivatives, polyethylene glycol, aloe vera, Glucamate DOE 120 (a polyethoxylated glucose dioleate containing 120 ethoxy units in the polyethylene glycol moiety, available), Glucam E10 (a polyethoxylated methyl glucose containing 10 ethoxy units), Glucam E-20 (a polyethoxylated methyl glucose containing 20 ethoxy units in the polyethylene glycol moiety), Glucam P-10 (a polyethoxylated methyl glucose), Glucam P-20 (a polyethoxylated methyl glucose containing 20 propoxy units in the polyethylene glycol moiety), allantoin, alginates, monoester salts of sulfosuccinates, alphahydroxy fatty acids, esters of fatty acids, ceramides, and mixtures thereof. Broadly, the conditioning agents are used at a level of from about 0.5-20% by weight. The most preferred conditioning agents are mineral oil, glycerin and/or propylene glycol, and are usually employed at a level of from about 1-20% by weight, and more preferably from about 2-10% by weight.
Dye or pigment used in the compositions of the invention may be any organic or inorganic dye or pigment which is a chemically acceptable trace constituent on epidermal surfaces. Generally, dyes which are useful in the composition of this invention include 7 FDandC dyes available that are generally recognized as safe. Although any number of colorants may be used, these dyes are preferred due to their relative acceptability in various solid and liquid food systems. Generally, dyes or pigments used in the invention are present in a concentration ranging from about 0.001 to about 0.01 wt %.
Chelating agents or sequestrants can be useful stabilizing agents in the invention particularly when a complexed form of iodine is present. Commonly available chelating agents can be used in the invention including both inorganic and organic chelating agents. Organic chelating agents include alkyl diamine polyacetic acid, chelating agents such as EDTA (ethylenediamine tetracetic acid tetrasodium salt), acrylic acid and polyacrylic acid type stabilizing agents, phosphonic acid and phosphonate type chelating agents and others. Preferable organic sequestants include phosphonic acids and phosphonate salts including 1-hydroxy ethylidene-1, 1-diphosphonic acid, amino [tri(methylene phosphonic acid)], ethylene diamine [tetra(methylene-phosphonic acid)], 2-phosphonobutane-1,2,4-tricarboxylic acid as well as alkali metal salts, ammonium salts, or alkyl or alkanol amine salts including mono-, di- or triethanol amino salts. Inorganic chelating agents include commonly available polyphosphate materials such as sodium pyrophosphate, sodium or potassium tripolyphosphate along with cyclic or higher polyphosphate species. Preferably, such a sequestering agent is used at a concentration ranging from about 0.05 wt % to about 0.5 wt % of the composition.
Commonly available organic acids that can be used in the invention include benzoic acid, mandelic acid, sorbic acid, citric acid, lower alkanoic acids and their food-grade salts, such as the sodium potassium or ammonium salts thereof. These organic acids, their salts, or mixtures thereof are present in the composition in an amount between about 0.010 to 0.5 percent by weight, preferably from 0.050 to 0.20 percent by weight. The presently preferred organic acids are mandelic acid, benzoic acid and sorbic acid, with benzoic acid suitably present as sodium benzoate and sorbic acid suitably present as the free acid. Each of these acids, or their salts, and others, alone or in combinations, can be incorporated into the compositions contemplated in this invention.
Commonly available film forming agents that can be used in the invention include polyvinylpyrrolidone (PVP), PVP derivatives like alkylated PVP, PVP copolymers like PVP/dimethylaminoethylmethacrylate/polycarbamyl/polyglycol ester, Poloxamers, polyethylene glycol, polyvinyl alcohol, polysulfonic acid, water soluble cellulose derivatives, acrylate copolymers such as acrylate/hydroxyester acrylate copolymers, collagen and collagen derivatives, keratin, polyquaternium compounds, interpenetrating polymers of polycrylic acid and a block terpolymer of propylene oxide and ethylene oxide with reverse thermal gelation properties, polyvinyl methacrylate derivatives and tosamide epoxy resins.
Various formulations anticipated under the teachings of this application may require two separate phases or components. This is understood and it is incorporated into the teachings of this application. Two components products that are activated prior to use by admixture are commonly available. Cheeseborough Pond""s USA Company (CPUSA) has successfully introduced Mentadent(copyright) toothpaste. Consequently, CPUSA has commercialized a mouthwash and handcream that both rely upon admixture prior to use. In many instances, pharmacists compound a product and package it into a dispenser for subsequent use by the consumer. It is anticipated that many of the potential formulations contemplated under this application will fall into such a category.
Any method to generate molecular iodine, in situ, may be used to formulate a dermatological non-staining topical iodine antimicrobial composition in accordance with the present invention including the method of generating molecular iodine taught in copending patent application Ser. No. 960,149 filed Oct. 29, 1998 the disclosure of which is herein incorporated by reference. As taught in the foregoing patent application molecular iodine may be generated, in situ, by combining an iodine reductant in concert with an oxidant iodine species having a positive oxidation state and a buffering agent for causing oxidation-reduction reactions to occur in which the iodine reductant is reduced to molecular iodine or in which the oxidant iodide species is oxidized into molecular iodine. The iodine reductant may be selected from the group consisting of iodide, sodium thiosulfate, ascorbate, lactose, reducing sugars and imidazole whereas the oxidant iodine species may be selected from the group consisting of hydrogen peroxide, iodate, alkali salts of peroxide such as calcium peroxide, peroxidase, ascorbic acid and/or other pharmaceutically acceptable organic acids with an oxidation potential greater than xe2x88x920.54 electron volts. The preferred formulation combines an iodide and an iodate with a suitable buffer to control pH preferably in two phases with the first phase incorporating the iodate and iodide in a first buffer to form a basic pH and with the second phase being the activator phase which is highly buffered with an acidic buffer such as, for example, citric acid, phosphoric acid and phthallic acid. The iodide in the preferred formulation may be selected from the group consisting of sodium iodide, potassium iodide, ammonium iodide, calcium iodide, and magnesium iodide and the iodate of such formulation may be selected from the group consisting of calcium iodate, magnesium iodate, potassium iodate, and sodium iodate. The preferred range of the iodide to iodate species in the preferred formulation is from ⅓ to {fraction (1/12)}. The pH of the iodate/iodide phase should be no less than 8.0 and preferably greater than 8.5. The iodate/iodide phase can assume a diverse range of compositions: liquid, gel, ointment or cream. The critical aspect of the iodate/iodide phase is that these two active agents are stable. Prior to use, the iodate/iodide phase is combined with a second activator phase. The activator phase is highly buffered at a pH that is less than 5.0. The pH of the mixture of these two phases must be controlled such that the final pH is 5.0 or less. As a consequence of altering the pH environment, molecular iodine is generated from the iodate and iodide. An example of such a composition is given in Example 12 below.
The following examples are illustrative of the teachings of this application and are not meant to limit the invention in any manner.